Fatty acid synthase (FAS), the multifunctional enzyme required for de novo lipogenesis, is altered in common metabolic diseases. We recently discovered that the products of the FAS reaction preferentially activate peroxisome proliferator-activated receptor alpha (PPARalpha) in liver. PPARs are nuclear receptors known to affect glucose and lipid metabolism, and they represent attractive targets for diet and drug therapy to alter the abnormal milieu associated with metabolic diseases. We have now generated several new animal models using Cre-Lox technology and demonstrated that FAS also appears to affect PPARalpha-dependent processes in macrophages, endothelium and hypothalamus with striking tissue-specific effects on vascular disease, inflammation (including susceptibility to endotoxin-induced death), and obesity. This project will test the hypothesis that de novo lipogenesis mediated by FAS modulates susceptibility to metabolic disorders associated with inflammation such as atherosclerosis, obesity and fatty liver in part by activating PPARalpha. We will pursue the following specific aims: 1. To determine in mice with FAS inactivation in macrophages (FASKOM mice) if protection from vascular disease is mediated by macrophage LXRalpha, another nuclear receptor. 2. To determine if endotoxin-induced death in mice with FAS inactivation in endothelium (FASKOE mice) is prevented by PPARalpha activation and if diet-induced atherosclerosis is accelerated in these mice with an increased response to inflammatory stimuli. 3. To determine if mice with FAS inactivation in hypothalamus (FASKOHyp mice) with decreased food intake are resistant to diet-induced obesity and if the hypophagic phenotype in these mice can be reversed by PPARalpha activation. 4. To identify potential endogenous PPARalpha ligands produced by FAS by comparing PPARalpha-associated lipid spectra between control mice and mice with FAS inactivation in liver (FASKOL mice). Obesity and its co-morbidities represent an enormous public health problem. Findings from these studies have the potential to establish novel pharmacologic and dietary approaches for the treatment of common metabolic disorders associated with obesity.